1. Field of the Invention
This invention relates to new and useful 1,4-dihydropyridine derivatives having the promoting activity of some antitumor agents against various kinds of tumor cells including multiple drug resistant cells and also to their use, and further, to process for the preparation of the novel derivatives.
2. Description of the Prior Art
Research is ongoing to stamp out cancerous growth by using various novel antitumor agents. However, the appearance of resistance to antitumor drugs is a serious problem in the clinical treatment of various tumors and therefore, the circumvention of such resistance is an important subject in the cancer chemotherapy.
Further, there are some intricate factors which make this problem more difficult to solve. In other words, tumor cells resistant to one of the antitumor agents show crossresistance to other antitumor agents (Multiple Drug Resistance: MDR), and overcoming this type of resistance is more difficult in clinical cancer chemotherapy.
Tsuruo et al (CANCER RES., 44, 4303, 1984; 43, 2267, 1983) reported that the drugs used clinically as a calcium channel-blocker, calmodulin inhibitor and antiarrhythmic agent promoted the activity of antitumor gents against resistant tumor cells. Practically, it was found that verapamil, caroverine, clomipramine, trifluoperazine, prenylamine, No. 233 and quinidine enhanced the activity of antitumor agents in vitro against the resistant sub-lines of mouse leukemia cells (P388/VCR, P388/ADR) and also verapamil enhanced the antitumor activity in vivo.
Tsuruo et al (CANCEL RES., 43, 2905, 1983) also reported that diltiazem and nicardipine as a calcium influx antagonist and quinidine as an antiarrhythmic agent promoted the activity of antitumor agents against mouse P388 cells resistant to VCR or ADR (P388/VCR, P388/ADR) in vitro and in vivo.
Promoting agents of antitumor activity reported so far mainly belong to the class of calcium antagonists or blockers. Intracellular calcium ion is the chemical mediator which carries on the physiological function in some particular tissues, that is, plays an important role in the excitation-contraction coupling of heart muscle and also, in the excitation-contraction coupling of vascular smooth muscle. Intracellular distribution and transport of calcium ion play a key role in their physiological function. The pharmacological action of various calcium antagonists is induced as a consequence of inhibition of calcium influx or function.
However, with respect to therapeutic efficacy of the calcium blockers as a promotor of antitumor agents, the striking action of these calcium blockers becomes a factor restricting their usefulness due to serious side-effects and therefore, limits their clinical application.